BREAST CANCER PROGRAM (BCP) PROJECT SUMMARY The main goals of the Breast Program (BCP) are to advance the understanding of breast cancer development, and the prevention and treatment of breast cancer; to translate laboratory discoveries to clinical practice; to facilitate intra-programmatic and inter-programmatic interactions; and to provide an enriched learning environment for students and postdoctoral medical and laboratory-based trainees. The Program has 27 members (22 Research members and 5 Clinical members) and shares 2 members with the Cell Signaling and Metabolism Program and one member with Cancer Cell and Gene Therapy Program. Jeffrey Rosen, PhD is the Leader of BCP, and Mothaffar Rimawi, MD, the Co-Leader. BCP includes both a strong basic science group and a clinical breast center that has a large and active clinical and translational program. As of July 2019, the Program has total direct funding of $17.4 million, of which $14.2 million is peer reviewed including $6.3 million from the NCI. In the last 5 years, members of the Program published 301 cancer-related manuscripts in peer-reviewed journals of which 36% represented intra-programmatic, 21% inter-programmatic, and 65% inter-institutional collaborations. The BCP is organized around 4 Research Themes: (1) Stem Cells, (2) Treatment Resistance, (3) Cross Talk and Signaling, and (4) Metastasis and the Tumor Microenvironment. Translation to the clinic is an integral component of all of these Themes. Our clinical trial portfolio is robust and highly translational. Our investigators designed and led national and international trials that have the potential to alter the way we understand and treat breast cancer. BCP investigators translated and led several laboratory discoveries into national and international clinical trials including 2 trials at the cooperative group level, 2 trials with the TBCRC, and one global trial. The impact of those trials is likely to alter the way we treat breast cancer. Major accomplishments of the BCP are: (1) The development of proteogenomics as both a discovery and diagnostic tool that may identify new therapeutic targets and hypotheses in treatment-resistant advanced breast cancer, (2) The development of novel small molecule therapeutics to target the unfolded protein response in combination with chemotherapy in breast cancer, and (3) New insights into the role of RNA splicing in breast cancer progression. Other achievements include: studies to confirm mechanisms of resistance to endocrine and HER2 targeted therapies, the construction of a unique multiparameter molecular classifier to identify patients whose tumors can be safely treated with target therapy alone, the identification of novel targetable vulnerabilities in triple-negative breast cancer (TNBC), the elucidation of signaling cascades involved in bone micrometastasis, and the definition of 2 ?myeloid subtypes? that contribute to the therapeutic response to immune checkpoint blockade in TNBC. Several of these observations have formed the basis for the renewal of a Specialized Program of Research Excellence (SPORE) application that has been continuously funded for 27 years.